The long-term goals of this study are: 1) to reveal the cellular basis of exercise intolerance and disability that occurs with age and 2) to test interventions that reverse the muscle cell dysfunction and rejuvenate exercise function to reverse the disability of the elderly. Exercise inefficiency has long been attributed to decreased contractile efficiency but new evidence points to a key role of mitochondrial dysfunction in this disability. This study proposes to first test this central role of mitochondrial dysfunction in exercise inefficiency with age using innovative non-invasive methods applied to exercising human muscle in vivo. Aim #1 determines the impact of mitochondrial energy uncoupling on muscle efficiency in old muscle. This test is possible using innovative optical and magnetic resonance spectroscopic.techniques that quantitatively measure - for the first time - mitochondrial energy coupling (ATP/O2) in vivo in single human muscles with age. The second innovation is to combine these non-invasive tools with rigorous biomechanical measurements on human muscle in vivo to determine the efficiency of exercising muscle (Work/O2) and the contractile elements (Work/ATP). Together these measurements will provide the first direct measure of the role of mitochondrial and contractile dysfunction in the debilitating loss of performance in single human muscles with age. The second goal of this proposal is to test whether exercise training can rejuvenate mitochondria and improve exercise efficiency in elderly muscle. Aim #2 tests a novel resistance training approach to activate mitochondrial adaptation as a means of reversing mitochondrial dysfunctionand exercise inefficiency to improve the disability of the elderly. . The clinical implication of this research is the development of a non-invasive measurement that isdiagnostic of the cellular basis of exercise dysfunction. Such an in vivo measurement would permit targeting interventions to individuals with the most affected muscles to reverse the functional loss that is a leading cause of disability in the elderly. [unreadable] [unreadable] [unreadable]